Cav1.2 calcium channels are critical for controlling cardiac excitability and excitation-contraction coupling in the heart, while their malfunctions lead to cardiac diseases. Cav beta-subunits are powerful natural modulators of the channel. Investigation of molecular correlates of beta-subunit modulation of the channel is crucial from the pharmacological standpoint because it holds promise of new avenues in drug discovery. From the C-tail of the major human cardiac beta2 subunit we have derived a previously unknown 41-amino acid peptide, which stimulates the channel activity, and identified its targeted structure in the channel. Results of this study are used now to engineer the interacting peptides with an aim to reveal structural principles of new potential beta-subunit-based drug(s). Another important regulator of Cav1.2 calcium channels is the calcium-sensing signaling peptide calmodulin. It plays a crucial role in negative feedback regulation of the channel activity preventing highly toxic calcium overload of cardiac cells during action potential. We have discovered the ability of calmodulin to modulate calcium channel expression and activity in a specific way in the absence of beta subunits. Results of this study open new perspectives for a genetically encoded correction of impaired channel functions in cardiovascular diseases. Using laser-capture microdissection of immunohistochemically-identified atrial and ventricular cells from explanted (ischemic cardiomyopathy) and rejected for transplantation healthy hearts, we have identified human cardiac genes that are significantly affected by cardiomyopathy in the atrium (12 genes) and left ventricle (63 genes). Our study revealed new unexpected targets that will facilitate drug discovery to combat this major cardiac disease. Also completed is the study of the effects of three major beta-subunits on the distances between and within the proteins composing calcium channels in their natural clusters. The arrangement of these molecules is estimated with a sub-nanometer precision using, for the first time, the three-color FRET microscopy technique and mathematical procedures developed in the lab. This study revealed an important property of human beta subunits to direct the arrangement of the channel clusters in a vascular and cardiac manner, which could explain, in part, the differences in vascular and cardiac EC-coupling.